Metalloproteinases are a superfamily of proteinases (enzymes) named for their dependence on a metal ion (zinc) in the active site.
The matrix metalloproteinases (MMPs) form a metalloproteinase sub-family having as one of major biological function to catalyse the breakdown of connective tissue or extracellular matrix through their ability to hydrolyse various components of the tissue or matrix, such as collagens, gelatins, proteoglycans, fibronectins and elastin.
The matrix metalloproteinase family is further divided according to their function and substrates (Visse al., 2003, Circ. Res., 92: 827-839) and comprises collagenases (MMP-1, MMP-8, MMP-13 and MMP-18), gelatinases (MMP-2 and MMP-9), stromelysins (MMP-3, MMP-10 and MMP-11), membrane-type MMPs (MT-MMP-1 to MT-MMP-6 and MMP-14, MMP-15, MMP-16, MMP-17, MMP-24 and MMP-25), matrilysins (MMP-7 and MMP-26) and other unclassified MMPs such as metalloelastase (MMP-12), enamelysin (MMP-20), epilysin (MMP-28), MMP-19, MMP-22 and MMP-23.
Apart from their role in degrading connective tissue, MMPs are involved in the biosynthesis of TNF-alpha and in the post-translational proteolysis processing, or shedding of biologically important membrane proteins (Hooper et al., 1997, Biochem J., 321: 265-279). MMPs for example contribute to the local growth and spread of malignant lesions and therefore have been a target for anti-tumor drug development (Fingleton et al., 2003, Expert Opin. Ther. Targets, 7(3):385-397. Disorders such as inflammatory disorders like arthritis (Clark et al., 2003, Expert. Opin. Ther Targets, 7(1):19-34), respiratory disorders such as emphysema, arteriosclerosis (Galis et al., 2002, Circ. Res., 90:251-262), neurological disorders such as degenerative nervous system diseases, multiple sclerosis (Leppert et al., 2001, Brain Res. Rev., 36:249-257), periodontitis (Ingman et al., 1996, J. Clin. Periodontal., 23:127-1132), pre-term labor (Makratis et al., 2003, J. Matern Fetal & Neonatal Medicine, 14(3): 170-6) and wound healing have been demonstrated to be associated with MMPs expression and/or activity.
A recently defined subset of the metalloproteases, the cell-associated A Desintegrin And zinc Metalloprotease (ADAM) family has emerged as an attractive therapeutic target, notably for cancer. At least twenty-three distinct ADAMs have been identified thus far. ADAM-17, also known as tumor necrosis factor-alpha converting enzyme (hereinafter “TACE”), is the most well known ADAM.
TACE is responsible for cleavage of cell bound tumor necrosis factor-alpha (“TNF-α). TNF-α is implicated in many infectious and autoimmune diseases. Moreover, TNF-α is the prime mediator in the inflammatory response seen in sepsis and septic shock. Several TACE inhibitors have been developed and reported in Watson, 2002, IDrugs, 5(12):1151-1161.
A wide variety of matrix metalloproteinase inhibitors (MMPIs) has been developed (Skiles et al., 2001, Current Medicinal Chemistry, 8, 425-474; Henrotin et al, 2002, Expert Opin. Ther. Patents, 12(1):29-43). However, many MMPIs exhibit a muscoskeletal syndrome (tendonitis, fibroplasias, mylasia, arthralasia) as a dose-limiting side effect. It has been proposed that inhibition of MMP-1 or MMP-14 may be responsible for these effects.
WO 01/87844 discloses hydroxamic acid and carboxylic acid derivatives with MMP and TNF inhibitory action for use in the treatment of cancer, inflammation, or an autoimmune, infectious or ocular disease.
WO 2004/006926 discloses sulphonylpiperidine derivatives containing an aryl or heteroaryl group for use as matrix metalloproteinase (MMP) inhibitors, in particular TACE.
Therefore, there is an increasing need to develop matrix metalloproteinase inhibitors with a well-defined specificity profile.
Specific inhibitors, especially towards MMP-1, have been reported, including MMP-13 inhibitors (Stotnicki et al., 2003, Current Opinion in Drug Discovery and Development, 6(5):742-759), MMP-12 inhibitors (Expert. Opin. Ther. Patents, 2004, 14(11):1637-1640), MMP-2 and MMP-9 inhibitors (Wada et al., 2002, J. Biol. Chem. 45: 219-232). The high relevance of the metalloproteinase pathway in some widely spread diseases stresses the need to develop inhibitors, including selective inhibitors of MMPs, especially of MMP-12.
Since excessive TNF-α production has been noted in several disease conditions also characterized by MMP-mediated tissue degradation, compounds which inhibit MMPs and/or TNF-α production may also have a particular advantage in diseases where both mechanisms are involved.